Schizophrenia research · 2020
Age dependent association of inbreeding with risk for schizophrenia in Egypt.
СтатьяПоддержка NIH: внешняя программаПоддержка исследования: вне правительства СШАНазвание и аннотация: Перевод в очереди
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McClain Lora, Mansour Hader, Ibrahim Ibtihal, Klei Lambertus, Fathi Warda, Wood Joel, Kodavali Chowdari, Maysterchuk Alina, Wood Shawn, El-Chennawi Farha, Ibrahim Nahed, Eissa Ahmed, El-Bahaei Wafaa, El Sayed Hanan, Yassein Amal, Tobar Salwa, El-Boraie Hala, El-Sheshtawy Eman, Salah Hala, Ali Ahmed, Erdin Serkan, Devlin Bernie, Talkowski Michael, Nimgaonkar Vishwajit
Аннотация
BACKGROUND: Self-reported consanguinity is associated with risk for schizophrenia (SZ) in several inbred populations, but estimates using DNA-based coefficients of inbreeding are unavailable. Further, it is not known whether recessively inherited risk mutations can be identified through homozygosity by descent (HBD) mapping.
METHODS: We studied self-reported and DNA-based estimates of inbreeding among Egyptian patients with SZ (n = 421, DSM IV criteria) and adult controls without psychosis (n = 301), who were evaluated using semi-structured diagnostic interview schedules and genotyped using the Illumina Infinium PsychArray. Following quality control checks, coefficients of inbreeding (F) and regions of homozygosity (ROH) were estimated using PLINK software for HBD analysis. Exome sequencing was conducted in selected cases.
RESULTS: Inbreeding was associated with schizophrenia based on self-reported consanguinity (χ2 = 4.506, 1 df, p = 0.034) and DNA-based estimates for inbreeding (F); the latter with a significant F × age interaction (β = 32.34, p = 0.0047). The association was most notable among patients older than age 40 years. Eleven ROH were over-represented in cases on chromosomes 1, 3, 6, 11, and 14; all but one region is novel for schizophrenia risk. Exome sequencing identified six recessively-acting genes in ROH with loss-of-function variants; one of which causes primary hereditary microcephaly.
CONCLUSIONS: We propose consanguinity as an age-dependent risk factor for SZ in Egypt. HBD mapping is feasible for SZ in adequately powered samples.
METHODS: We studied self-reported and DNA-based estimates of inbreeding among Egyptian patients with SZ (n = 421, DSM IV criteria) and adult controls without psychosis (n = 301), who were evaluated using semi-structured diagnostic interview schedules and genotyped using the Illumina Infinium PsychArray. Following quality control checks, coefficients of inbreeding (F) and regions of homozygosity (ROH) were estimated using PLINK software for HBD analysis. Exome sequencing was conducted in selected cases.
RESULTS: Inbreeding was associated with schizophrenia based on self-reported consanguinity (χ2 = 4.506, 1 df, p = 0.034) and DNA-based estimates for inbreeding (F); the latter with a significant F × age interaction (β = 32.34, p = 0.0047). The association was most notable among patients older than age 40 years. Eleven ROH were over-represented in cases on chromosomes 1, 3, 6, 11, and 14; all but one region is novel for schizophrenia risk. Exome sequencing identified six recessively-acting genes in ROH with loss-of-function variants; one of which causes primary hereditary microcephaly.
CONCLUSIONS: We propose consanguinity as an age-dependent risk factor for SZ in Egypt. HBD mapping is feasible for SZ in adequately powered samples.